NO115786B - - Google Patents
Info
- Publication number
- NO115786B NO115786B NO16489266A NO16489266A NO115786B NO 115786 B NO115786 B NO 115786B NO 16489266 A NO16489266 A NO 16489266A NO 16489266 A NO16489266 A NO 16489266A NO 115786 B NO115786 B NO 115786B
- Authority
- NO
- Norway
- Prior art keywords
- nystatin
- organic solvent
- approx
- fermentation
- mixture
- Prior art date
Links
- 229960000988 nystatin Drugs 0.000 claims description 16
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000000855 fermentation Methods 0.000 claims description 6
- 230000004151 fermentation Effects 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 241000187310 Streptomyces noursei Species 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000002152 aqueous-organic solution Substances 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/24—Apparatus using programmed or automatic operation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Fremgangsmåte for utvinning av nystatin. Method of extraction of nystatin.
Denne oppfinnelse angår fremstilling This invention relates to manufacturing
av det antifungale antibiotikum fungicidin, (nystatin) ved en fremgangsmåte ved hvilken det ønskede produkt fås med godt utbytte og av bra renhet. of the antifungal antibiotic fungicide, (nystatin) by a method by which the desired product is obtained in good yield and of good purity.
Antibiotikumet fungicidin (nystatin) og dets fremstilling av Streptomyces noursei er beskrevet i engelsk patent nr. 714 189. Se også E. L. Hazen og R. Brown: «Fungicidin, An Antibiotic Produced by a Soil Actinomycete», Proe. Soc. Exptl. Biol. Med. 76:93 (1950) og R. Brown, E. L. Hazen og A. Mason: «Effeet of Fungicidin (Nystatin) in Mice Injected with Lethal Mixtures of Aureomycin and Candida albicans», Science The antibiotic fungicide (nystatin) and its production by Streptomyces noursei is described in English patent no. 714 189. See also E. L. Hazen and R. Brown: "Fungicidin, An Antibiotic Produced by a Soil Actinomycete", Proe. Soc. Exptl. Biol. With. 76:93 (1950) and R. Brown, E. L. Hazen and A. Mason: "Effeet of Fungicidin (Nystatin) in Mice Injected with Lethal Mixtures of Aureomycin and Candida albicans", Science
117:609 (1953). Dette antibiotikum kalles i den følgende beskrivelse bare «nystatin». 117:609 (1953). This antibiotic is called simply "nystatin" in the following description.
Rå konsentrater av nystatin kan frem-stilles ved at den fraskilte mycelium ekstraheres med flere porsjoner metanol, og at metanoloppløsningen deretter felles fraksjonert med etylacetat, hvoretter utfellingen vaskes med 0,85 pst.'s NaCl-opp-løsning, løses opp igjen i metanol og atter felles fraksjonert ved hjelp av eter, eller kulturvæsken med mycelium ekstraheres med et organisk oppløsningsmiddel som er ikke-blandbart med vann. Se herom ovennevnte engelske patent nr. «714 189. Av det resultererende rå konsentrat kan det opp-nås små utbytter av aktivt krysetallinsk materiale ved fordeling mellom butanol og saltoppløsning, og ved partiell utfelling fra metanol. Krystallinsk nystatin av stor renhet er fått ved å fordele delvis renset ny-statinkonsentrat i et tofaset system, som er fått ved å blande n-butanol, metanol, vann og heksan, og la denne blanding stå og fordampe i luft inntil det samler seg krys-taller i mellomlagsflaten. Se James D. Dut-cher et al. «Antibiotics Annual» 1953—1954, side 191—194, Medical Encyclopedia., Inc., New York, N. Y. Crude concentrates of nystatin can be produced by extracting the separated mycelium with several portions of methanol, and then fractionating the methanol solution with ethyl acetate, after which the precipitate is washed with 0.85% NaCl solution, dissolved again in methanol and fractionated again using ether, or the culture liquid with mycelium is extracted with an organic solvent which is immiscible with water. See in this regard the above-mentioned English patent no. "714 189. Small yields of active crystalline material can be obtained from the resulting crude concentrate by partitioning between butanol and salt solution, and by partial precipitation from methanol. Crystalline nystatin of high purity is obtained by distributing partially purified nystatin concentrate in a two-phase system, which is obtained by mixing n-butanol, methanol, water and hexane, and allowing this mixture to stand and evaporate in air until a cross is collected -numbers in the interlayer surface. See James D. Dutcher et al. "Antibiotics Annual" 1953-1954, pages 191-194, Medical Encyclopedia., Inc., New York, N.Y.
De foran beskrevne metoder gir krystallinsk nystatin, men de har den ulempe åt det fås med meget litet utbytte og sammen med forurensninger. The methods described above give crystalline nystatin, but they have the disadvantage that it is obtained with a very low yield and together with impurities.
Dessuten er reaksjonene vanskelige å kontrollere, og ikke av den art som man ønsker å arbeide med i større skala. Moreover, the reactions are difficult to control, and not of the kind that one wants to work with on a larger scale.
Oppfinnerne har ved sine undersøkelser på området funnet at nystatin kan utvin-nes ved ekstrahering av den hele fermen-teringsmasse ved hjelp av et med vann blandbart organisk opløsningsmiddel, ved anvendelse av den nedenfor beskrevne fremgangsmåte. The inventors have found in their investigations in the area that nystatin can be recovered by extracting the entire fermentation mass with the aid of a water-miscible organic solvent, using the method described below.
Eksempel: Example:
Til den samlede mengde fermenterings-produkt som fås ved fermentering av Streptomyces noursei i et vandig nærings-medium av soyamel-glukose settes det et like stort volum isopropanol. Deretter sen-kes blandingens pH til ca. 5 ved hjelp av fosforsyre. Etter ca. 1 times omrøring heves pH til ca. 7 ved tilsetning av natri-umhydroksyd. Den resulterende oppløs-ning filtreres. Herved fjernes en stor del av forurensningene. Deretter fjernes iso-propanolen fra filtratet, fortrinsvis under vakuum ved en temperatur av ca. 30° C eller lavere. Når alkoholen fjernes, faller det ut et delvis krystallisert nystatin av 65—70 pst.'s renhet, med et utbytte av ca. An equal volume of isopropanol is added to the total amount of fermentation product obtained by fermentation of Streptomyces noursei in an aqueous nutrient medium of soy flour-glucose. The pH of the mixture is then lowered to approx. 5 using phosphoric acid. After approx. Stirring for 1 hour raises the pH to approx. 7 by adding sodium hydroxide. The resulting solution is filtered. This removes a large part of the pollutants. The iso-propanol is then removed from the filtrate, preferably under vacuum at a temperature of approx. 30° C or lower. When the alcohol is removed, a partially crystallized nystatin of 65-70 per cent purity falls out, with a yield of approx.
70—75 pst. Utfellingen filtreres eller sen-trifugeres fra, vaskes med litt vann, vaskes derpå med aceton, og tørkes. Metanol kan anvendes i stedet for isopropanol, men ut-byttet blir langt mindre, ned til en størrel-sesorden av ca. 50—55 pst. Det foretrekkes også å anvende isopropanol, eller normal propanol, i stedet for andre med vann blandbare organiske opløsningsmidler (f. eks. etanol, metanol, aceton, osv.) fordi propanolene fjerner (feller ut) langt mere av forurensningene, f. eks. av proteiner, sakkarider osv., som nedsetter et godt utbytte av nystatin som har god renhetsgrad. 70-75 per cent. The precipitate is filtered or centrifuged off, washed with a little water, then washed with acetone and dried. Methanol can be used instead of isopropanol, but the yield is far less, down to an order of magnitude of approx. 50-55 percent. It is also preferable to use isopropanol, or normal propanol, instead of other water-miscible organic solvents (e.g. ethanol, methanol, acetone, etc.) because the propanols remove (precipitate) far more of the contaminants , e.g. of proteins, saccharides, etc., which reduce a good yield of nystatin which has a good degree of purity.
Senkningen av pH ved tilsetning av surt stoff, så man får pH 4—6 og fortrinsvis 4,5—5,5, hjelper til med å løse opp nystatinet i det vandig-organiske oppløs-ningsmedium. Reguleringen av pH til ca. 6,5—7,5, fortrinsvis 7, ved tilsetning av al-kalisk stoff hjelper til med å felle ut nystatinet når det organiske oppløsnings-middel fjernes. Hvilke som helst ekviva-lente sure og alkaliske stoffer kan brukes for regulering av pH til de ovennevnte ønskede verdier. Mengden av med vann blanbart organisk oppløsningsmiddel som anvendes sammen med den nystatinholdige blanding kan variere fra ca. 40—75 pst. eller mere, beregnet i forhold til det samlede volum av oppløsningsmiddel og reaksjonsblanding. De fordelaktigste meng-der som kan anvendes av et spesielt opp-løsningsmiddel i forbindelse med en spesi-ell reaksjonsblanding kan fastsettes ved forutgående forsøk. The lowering of the pH by the addition of an acidic substance, so that a pH of 4-6 and preferably 4.5-5.5 is obtained, helps to dissolve the nystatin in the aqueous-organic dissolution medium. The regulation of pH to approx. 6.5-7.5, preferably 7, when adding an alkaline substance helps to precipitate the nystatin when the organic solvent is removed. Any equivalent acidic and alkaline substances can be used for regulating the pH to the above desired values. The amount of water miscible organic solvent used together with the nystatin-containing mixture can vary from approx. 40-75 percent or more, calculated in relation to the total volume of solvent and reaction mixture. The most advantageous amounts that can be used of a special solvent in connection with a special reaction mixture can be determined by prior experiments.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE1253765A SE312199B (en) | 1965-09-27 | 1965-09-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO115786B true NO115786B (en) | 1968-12-02 |
Family
ID=20295913
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO16489266A NO115786B (en) | 1965-09-27 | 1966-09-26 |
Country Status (9)
| Country | Link |
|---|---|
| BE (1) | BE687418A (en) |
| CH (1) | CH468193A (en) |
| DE (1) | DE1617966C3 (en) |
| DK (1) | DK115721B (en) |
| FI (1) | FI47527C (en) |
| GB (1) | GB1137409A (en) |
| NL (1) | NL6613398A (en) |
| NO (1) | NO115786B (en) |
| SE (1) | SE312199B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2333958A (en) * | 1998-02-09 | 1999-08-11 | Prior Clave Ltd | A method of operating an autoclave. |
| IT201600131201A1 (en) | 2016-12-27 | 2018-06-27 | W & H Sterilization Srl | PERFORMED THERMODYNAMIC CYCLE STERILIZATION SYSTEM AND RELATED METHOD |
-
1965
- 1965-09-27 SE SE1253765A patent/SE312199B/xx unknown
-
1966
- 1966-09-22 GB GB4233266A patent/GB1137409A/en not_active Expired
- 1966-09-22 NL NL6613398A patent/NL6613398A/xx unknown
- 1966-09-22 FI FI249166A patent/FI47527C/en active
- 1966-09-23 DE DE19661617966 patent/DE1617966C3/en not_active Expired
- 1966-09-26 CH CH1383466A patent/CH468193A/en unknown
- 1966-09-26 NO NO16489266A patent/NO115786B/no unknown
- 1966-09-26 BE BE687418D patent/BE687418A/xx unknown
- 1966-09-27 DK DK500966A patent/DK115721B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH468193A (en) | 1969-02-15 |
| BE687418A (en) | 1967-03-01 |
| GB1137409A (en) | 1968-12-18 |
| DE1617966A1 (en) | 1971-04-15 |
| NL6613398A (en) | 1967-03-28 |
| FI47527C (en) | 1974-01-10 |
| DE1617966C3 (en) | 1975-04-03 |
| DK115721B (en) | 1969-11-03 |
| DE1617966B2 (en) | 1974-08-01 |
| FI47527B (en) | 1973-10-01 |
| SE312199B (en) | 1969-07-07 |
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